Epinephrine – Mobilization of Cytotoxic Leukocytes
A Journal of Immunology study suggests that during acute stress the hormone epinephrine (adrenaline) is rapidly causing demargination of cytotoxic effector leukocytes from the marginal pool of blood vessels, thus releasing these cells into the circulation, which, in turn, may provide immediate protection from invading pathogens.
Acute stress in humans is known to cause a rapid and transient leukocytosis, presumably reflecting the demargination of these cells from the marginal pool. This immediate demargination of leukocytes from vascular endothelial cells is promoted by sympathetic nervous system (SNS) catecholaminergic activity, i.e. systemic or local release of catecholamines (mostly epinephrine and norepinephrine), which, in turn, stimulate PBMCs that express predominantly high-affinity β2-adrenoceptors. Noteworthy, this mobilization of leukocytes is selective and primarily affects, among others, effector CD8+ T cells and natural killer (NK) cells.
It is important to note, however, this is addressing acute conditions, i.e. acute stress. Thus, for example, catecholamines appear to have a dual effect on NK cells. On one hand, catecholamines (mostly epinephrine) mediate an acute, short lasting, and transient increase of NK cells numbers due to their mobilization from depots (see above); on the other hand, however, catecholamines appear to mediate, chronically, an inhibition of NK cell activity. In patients with heart failure, a disease characterized by chronically high levels of plasma NE, these levels correlate with anergy in the cytotoxicity of circulating NK cells.
In the Journal of Immunology study, Dimitrov, Lange and Born demonstrate that an infusion of adrenal medullary hormone epinephrine in healthy human subjects selectively increases the numbers of circulating cytotoxic leukocytes, including effector CD8+ T cells, gamma/delta T cells, NKT-like cells, cytotoxic NK cells, and proinflammatory monocytes. A specific increase was found in immune subpopulations with cytotoxic effector potential, namely, effector CD8+ T cells (CD3+CCR7−CD45RA+), γ/δ T cells (CD3+CD4−CD8−), NKT-like cells (CD3+CD56+), cytotoxic NK cells (CD16+CD56dim), and proinflammatory monocytes (CD14dimCD16+).
Per the authors, the fast mobilization and recovery of cytotoxic cell counts observed in this and previous studies after stress, exercise, or catecholamine infusion reflects the demargination of T cells, NK cells, and monocyte subpopulations.
These effects are caused by adrenal medullary hormone epinephrine binding to to β2-adrenoceptors on peripheral blood mononuclear cells, with high and intermediate levels of β2-adrenoceptor expression on NK cells and cytotoxic T cells, respectively.
The conditions established in this study mimic those observed during acute stress. In contrast, as mentioned above, chronic beta-adrenoceptor stimulation, as addressed in previous studies, may exert opposite effects, with selectively reduced numbers of circulating NK cells and CD8+T cells.
It is concluded that during an acute stress, increased epinephrine release likely serves to selectively recruit cytotoxic effector cells as the first line of defense against pathogens, a mechanism that allows for efficient surveillance of tissues and rapid accumulation at sites of injury and infection.
SOURCE: J Immunol 2010, 184: 503
Updates
A PLOS One 2015 study by Marc Bigler et al. reported the effects of 3,4-methylenedioxymethamphetamine (MDMA), methylphenidate (MPH) in healthy volunteers. 3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) and methylphenidate (MPH,“Ritalin1”) are widely used psychoactive substances that induce an endocrine and cardiovascular stress response that has been extensively studied.
MDMA, MPH, and the combination of the two drugs induced an increase in systolic blood pressure (SBP) and heart rate peaking three hours after drug administration. Immunologically, the most striking observation was a dramatic increase of NK cells within the lymphocyte compartment that was most pronounced upon exposure to combination treatment of MDMA and MPH. Importantly, NK cell increase correlated with the change in epinephrine levels, but not with the change of cortisol or norepinephrine.
The authors concluded that the MDMA/MPH > MDMA > MPH robustly induced stress response was characterized by rapid accumulation of mature and functional NK cells, i.e. enrichment of CD56dim NK cells in the peripheral circulation, which was associated with a strong epinephrine response.
A 2018 study by Rachel M. Graff et al. reported that β2-AR signaling is the primary mechanism by which the most stress-responsive lymphocyte and monocyte subtypes are mobilized to the bloodstream during exercise. The authors concluded that the preferential mobilization of NK-cells, non-classical monocytes and differentiated subsets of CD8+ T-cells with exercise is largely dependent on catecholamine signaling through the β2-AR.
According to these authors, this is the first study to show that those lymphocyte and monocyte subtypes considered to be highly ‘exercise responsive’ have the greatest dependency on β2-AR signaling for their mobilization to the bloodstream with exercise.
These findings provide mechanistic insights by which distinct lymphocyte and monocyte subtypes are preferentially mobilized to protect the host from anticipated injury or infection in response to an acute stress response.
Highlights
- Lymphocytes and monocytes are rapidly mobilized to blood at the onset of exercise.
- Mature subsets of CD8+ T-cells, NK-cells and monocytes are preferentially mobilized.
- β2-Andregrenic receptors (β2-ARs) mediate this preferential mobilization.
Another 2018 study by Nadia Agha et al. compared the effects of vigorous to moderate intensity exercise on the mobilization of CD34+ and CD133+ hematopoietic stem cells (HSCs) to the bloodstream in healthy volunteers, and examined the temporal response of HSC mobilization and plasma granulocyte-colony stimulating factor (G-CSF) levels both during and after exercise.
These authors reported that steady state vigorous but not moderate intensity exercise mobilized CD34+ and CD133+ HSCs to the peripheral blood compartment in healthy participants. They concluded that the mobilization of CD34+ HSCs with exercise is not dependent on circulating G-CSF and is likely due to the combined actions of β2-AR signaling and hemodynamic shear stress. This is perhaps the first report to indicate that CD34+ HSCs mobilized to the blood during exercise are done so via a β2-AR mediated pathway, independently of circulating G-CSF levels.
A 2025 study by Kyle Smith et al. investigated mechanisms governing immune cell mobilization in humans and the role of adrenergic signaling in anti-cancer responses to a murine lymphoma.
Background: Signaling through the β2-adrenergic receptor (β2-AR) mobilizes immune cells during exercise and is implicated in tumor lymphocyte infiltration.
β1 + β2-AR blockade reduced lymphocyte and NK-cell mobilization during steady-state exercise, while β1-AR blockade enhanced the mobilization of NK-cells. Combining a β1-AR antagonist with a phosphodiesterase-4 (PDE4) inhibitor during graded exercise further increased mobilization of CD8 + T-cells, γδ T-cells, and monocytes. Isoproterenol infusion also elevated lymphocyte and NK-cell levels similarly to exercise at 70 % VO2max.
In murine models of voluntary wheel running, β2-AR signaling and NK-cells were critical for exercise-induced protection against B-cell lymphoma, as β2-AR blockade or NK-cell depletion abrogated these effects.
The authors concluded that these findings highlight the pivotal role of β2-AR signaling in mobilizing cytotoxic immune cells and protecting against tumor progression through exercise, suggesting potential therapeutic strategies combining exercise with adrenergic modulation to enhance immune responses.
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